KR20140037879A - Dry-coated tablet containing tegafur, gimeracil and oteracil potassium - Google Patents

Abstract

The present invention provides a nucleated tablet comprising an inner core and an outer shell containing (a) tegapur, (b) gimeracil, and (c) potassium terasil as active ingredients.

Description

DRY-COATED TABLET CONTAINING TEGAFUR, GIMERACIL AND OTERACIL POTASSIUM}

TECHNICAL FIELD This invention relates to the nucleated tablet for oral administration containing tegapur, gimeracil, and oterasyl potassium.

The tegapur, gimeracil and orteracyl potassium combinations include tegapur, a prodrug of fluorouracil (5-FU), and gimeracil, a degradation inhibitor of 5-FU, and orerasil potassium, a phosphorylation inhibitor. It is an anti-tumor agent characterized by reducing anti-digestive toxicity while increasing antitumor effect, and is widely used in the clinical field as a cancer chemotherapy agent that can be administered orally (Patent Document 1).

Currently, the tegapur, gimeracil and orteracyl potassium blends are encapsulated under the name `` TS one blended capsule '' with a molar ratio of tegapur: gimeracil: oterathyl potassium of 1: 0.4: 1. A granule is marketed under the name of "TS source compounded granules" (patent document 2). However, capsules and granules may be difficult to swallow in elderly people with reduced swallowing function, and the oral disintegrating tablets that rapidly disintegrate in the oral cavity, which are easy to take even in swallowing difficulties, are required in the clinical field.

On the other hand, in general, the active ingredient exhibiting antitumor effect has a higher pharmacological activity as classified as extreme medicine, and tegapur is one of them, and its handling requires sufficient attention. If the active ingredient of the anticancer agent is exposed or is scattered due to cracking or breaking of the preparation, drug exposure may occur not only to the medical worker but also to the patient or medication assistant taking the medicine. Generally, in order to reduce drug exposure, the method of encapsulating a drug in a capsule containing gelatin or the like, or coating the drug as a tablet with sugar, a polymer or the like is used. However, since these techniques delay the disintegration of the formulation, rapid disintegration in the oral cavity cannot be expected.

In addition, in order to improve the disintegration property of the orally disintegrating tablet, a formulation with low strength is often used. In that case, the process of manufacture and distribution and the preparation by the automatic dispensing machine which falls from the height of about 1m normally, and distributes a chemical | medical agent are not tolerated, and a crack and a crack generate | occur | produce in a formulation, and the risk of exposure of a chemical to medical workers etc. increases. I am concerned.

Regarding the formulations containing tegapur, gimeracil and orerasyl potassium, for example, Patent Document 3 discloses a formulation of tegapur, gimeracil and orerasyl potassium formulations that are stable and orally administrable even under humidified conditions. There is a disclosure. However, this formulation is for the purpose of improving stability as a formulation, and does not take into consideration the dosage of patients, etc., who have difficulty swallowing. In addition, in order to improve the function such as disintegration of tablets, addition of disintegrants in addition to sugars that are stable leads to destabilization of the active ingredient. In addition, Patent Document 4 discloses an orally disintegrating tablet in which tegapur, gimerasil, and terrasil potassium are blended. However, the patent does not take measures against drug exposure by medical workers, caregivers, etc., even though the drug is a highly active anticancer agent.

Patent No. 2614164 International Publication 2009/084216 Japanese Patent Laid-Open No. 2010-235539 Publication of Chinese Patent Publication CN1660105A

As described above, the known tegapur, gimeracyl and oteracyl potassium combination formulations are known to reduce the drug exposure risk sufficiently, have sufficient tablet strength, and do not cause a decrease in drug delivery even when taken. Is required.

It is an object of the present invention to provide nucleated tablets of tegapur, gimeracil and oterasyl potassium combinations that have reduced drug exposure risk, rapid disintegration and sufficient tablet strength. Specifically, an object of the present invention is a combination of an inner core containing a shell having good moldability and an excellent disintegration property and an active ingredient, having a sufficient mechanical strength and rapidly disintegrating in the oral cavity while reducing the risk of drug exposure. To provide.

In order to solve the above problems, the present inventors attempted to prepare various orally administrable tegafur, gimeracil, and oteracyl potassium combination tablets.

As a result, the inner core containing tegapur, gimeracyl and octeracyl potassium, and the shell having a good formability and good disintegrating shell composed of specific additives have a sufficient mechanical strength, and thus the drug While reducing the risk of exposure, an agent that rapidly disintegrates in the oral cavity has been found to complete the present invention.

That is, the present invention provides the following nucleated tablets.

A nucleated tablet comprising (1) an inner core containing (a) tegapur, (b) gimeracil and (c) potassium terasil as active ingredients, and an outer shell.

(2) The nucleated tablet according to (1), which contains (a) tegapur, (b) gimeracil, and (c) potassium teracil in a molar ratio of 1: 0.4: 1.

(3) (1) or (2), wherein the active ingredient comprising (a) tegapur, (b) gimeracil, and (c) potassium terasil occupies 50% by mass to 100% by mass of the inner core component The nucleated tablet described in.

(4) (1) to (3), wherein the active ingredient comprising (a) tegapur, (b) gimeracil, and (c) potassium terasil occupies 70% by mass to 99% by mass of the inner core component. The nucleated tablet according to any one of the above.

(5) The nucleated tablet according to any one of (1) to (4), wherein the total content of the active ingredients (a) to (c) in the nucleated tablet is 10 to 60 mass%.

(6) The nucleated tablet according to any one of (1) to (5), wherein the shell contains one, two, or three of lactose, crystalline cellulose, and hydroxypropyl cellulose.

(7) The nucleated tablet according to (6), wherein the shell includes lactose and one or two of crystalline cellulose.

(8) The nucleated tablet according to (7), wherein the shell contains lactose and crystalline cellulose.

(9) The nucleated tablet according to (6), (7) or (8), further comprising a disintegrant in the outer shell.

(10) The nucleated tablet according to (9), wherein the disintegrant is selected from the group consisting of crospovidone, carmellose, corn starch, low-substituted hydroxypropyl cellulose, and partially alphaated starch.

(11) The nucleated tablet according to (10), wherein the disintegrant is crospovidone and / or partially alpha starch.

(12) The nucleated tablet according to any one of (1) to (11), wherein the shell contains 30 to 65 mass% of lactose.

(13) The nucleated tablet according to any one of (1) to (12), wherein the shell contains 30 to 50 mass% of crystalline cellulose.

(14) The nucleated tablet according to any one of (1) to (13), wherein the shell contains 2.5 to 15 mass% of crospovidone.

(15) The nucleated tablet according to any one of (1) to (14), wherein the shell contains 2 to 7.5% by mass of partially alphalated starch.

(16) The wear damage of the nucleus tablet (accumulated rotational speed of 100 revolutions) is 0.3% or less, and has a shell which does not substantially crack or crack in the drop test at a height of 1 m. The nucleated tablet according to any one of (1) to (15), wherein the disintegration time by is 120 seconds or less.

According to the present invention, by making the nucleus tablet and blocking the drug in the inner core, the active ingredient is not present on the surface of the tablet, which greatly reduces the risk of exposure to the drug by medical workers and the like. Can be realized. In addition, since separation of the inner core and the shell can reduce contact with an additive that promotes decomposition of the active ingredient, decomposition can be suppressed.

1 shows a schematic diagram of a cross section of a nucleated tablet.

In the present invention, the molar ratios of tegapur, gimeracil and potassium terasil potassium can be appropriately selected, but combinations of 1: 0.4: 1 each are preferred. The amounts of tegapur, gimeracyl and oteracyl potassium, which are active ingredients in the nucleated tablet of the present invention, vary depending on the dosage form, administration schedule, and the like, and are not particularly limited and may be appropriately selected. It is preferable to make the total content of a component about 10-60 mass%, It is more preferable to set it as 20-50 mass%, It is especially preferable to set it as 25-35 mass%.

Preferred nucleated tablets of the present invention are nucleated tablets having a shell having a degree of abrasion damage (accumulated rotational speed of 100 revolutions) of 0.3% or less, more preferably a shell having a degree of wear damage of 0.1% or less. "Abrasion damage degree" is a meaning generally used in the technical field of the formulation, that is, to know whether the molded tablet can withstand the vibration or shock in the subsequent process of coating, printing, packaging or market, distribution, Wear damage using a rotating drum is also a parameter evaluated by the amount of reduction in tablet weight by a tester and is an index of tablet strength. Specifically, the rotation speed of the drum with an electric motor (inner diameter 287 ± 4 mm) is adjusted to be 24 to 26 revolutions per minute, for example, in accordance with the reference information "Refining Wear Damage Test Method" of Japanese Pharmacopoeia 15th Amendment. In addition, the tablet weight after a fixed rotation was measured, and what calculated the percentage of reduction with respect to the tablet weight at the start is made into abrasion damage degree. In the present specification, the degree of abrasion damage when the cumulative rotational speed is set to 100 revolutions is shown and calculated from the tablet weight at 25 rpm and 4 minutes. The case where the wear damage of a cumulative rotation speed of 100 rotations is 0.3% or less is defined as high tablet strength. On the contrary, what is larger than 0.3% is defined as low tablet strength. The active ingredient contained in the present invention may be referred to as an anticancer agent, and in order to reduce the exposure risk even lower than a general drug, the tablet strength needs to be increased, so that the wear damage is set lower than that of a conventional formulation. This is good.

The preferred nucleated tablet of the present invention has an outer shell which is not substantially cracked or cracked in the drop test at a height of 1 m, and more preferably has an outer shell which is not substantially cracked or cracked in a drop test at a height of 2 m. It is a nuclear tablet. Here, a "fall test" is a test normally used in the technical field of a formulation, in order to know whether it can tolerate the vibration and shock in preparation by manufacture, distribution, etc., or an automatic distribution machine. Specifically, the tablet is naturally dropped onto the stainless steel plate from a height of 1 m to 2 m to confirm the cracking or cracking of the tablet and the rate of mass reduction before and after the test. In the present invention, "substantially no cracking or cracking" means that when the drop test is performed on five tablets, no cracking or cracking occurs at all, and the mass reduction rate in the five tablets is less than 0.1%. Means.

In the preferred nucleated tablet of the present invention, the disintegration time of the whole nucleated tablet is 120 seconds or less. Specifically, when the disintegration test is performed in accordance with the Japanese Pharmacopoeia 15th Amendment General Test Method Disintegration Test Method, the disintegration time is a nucleus well within 120 seconds. This disintegration time becomes like this. Preferably it is less than 95 second, More preferably, it is within 80 second. In the case of a fast disintegrating nucleated tablet in the oral cavity, the actual dissolution and disintegration time in the oral cavity is equivalent to or faster than the disintegration time in the disintegration test method due to friction in the oral cavity and addition of movement by the tongue. It may become. Further, a simple integration of the collapse test method is as follows. The tester is attached to the shrinkage and placed in a beaker and adjusted to perform a vertical motion smoothly at 29 to 32 reciprocations, amplitude 53 to 57 mm for 1 minute. When the tester is lowest, the bottom surface is 25 mm from the bottom of the beaker, and the amount of water placed in the beaker so that the upper surface of the tester coincides with the surface of the liquid when the tester is lowest. The temperature of the liquid is maintained at 37 ± 2 ℃. A sample schedule is put in the glass tube of a tester, a test board is put into a test liquid using water, and a vertical motion is performed. The time until the residue of a sample is no longer recognized in a glass tube is measured, and it is set as collapse time.

Disintegration of tablets in the oral cavity is highly dependent on a small amount of water, such as saliva, and a slight rubbing force between the tongue and the maxilla. Therefore, the disintegration test (the Japanese Pharmacopoeia 14 revised General Test Method Disintegration Test Method) as used for ordinary tablets does not reflect actual disintegration in the oral cavity. For this reason, ODT-101 (manufactured by Toyama Sangyo) and Trikov Tester (manufactured by Seiko Okada) has been developed and released as an oral disintegrating tablet tester, and by using them, considering the correlation with data of the sensory evaluation test by humans, It can be measured reproducibly and easily without individual differences (Ref. Narazaki R., Harada T., et al., Chem. Pharm. Bull., 52, 704-707 (2004)). The disintegration time measured by the oral disintegrating tablet tester ODT-101 of the nucleated tablet of the present invention is preferably 20 seconds or less, more preferably 16 seconds or less, and particularly preferably 14 seconds or less.

The preferred nucleated tablet of the present invention has a dissolution rate (CDHP, 15 minutes) measured by Japanese Pharmacopoeia General Test Method Dissolution Test Method 2 (50 min ⁻¹ , 900 mL of test solution water) of 90% or more, and 95% or more. More preferably, 97% or more is especially preferable.

Particularly preferred nucleated tablets of the present invention are nucleated tablets having a shell having a degree of wear damage (accumulated rotational speed of 100 revolutions) of 0.3% or less, having a disintegration time of 120 seconds or less according to the Japanese Pharmacopoeia General Test Method Disintegration Test Method. Preferably they are nucleated tablets having a shell having a wear damage of 100% of the nucleated tablet (accumulated rotational speed of 100) or less and having a disintegration time of 95 seconds or less by the Japanese Pharmacopoeia General Test Method Disintegration Test Method,

More preferably, the wear damage of the nucleus tablet (accumulated rotational speed of 100 revolutions) is 0.2% or less, and has a shell which does not substantially crack or crack in the drop test at a height of 1 m. It is a nucleus tablet whose disintegration time by a collapse test method is 95 seconds or less, More preferably, the abrasion damage degree (accumulation rotation speed 100 rotations) of a nucleus tablet is 0.2% or less, and it is substantially cracked in the fall test at 2 m in height, It is a nucleus tablet having a shell which does not cause cracking and has a decay time of 95 seconds or less by the Japanese Pharmacopoeia General Test Method Disintegration Test Method,

More preferably, the wear damage of the nucleus tablet (accumulated rotational speed of 100 revolutions) is 0.2% or less, and has a shell which is substantially free from cracking or cracking in the drop test at a height of 2 m. The disintegration time by the disintegration test method is 95 seconds or less, the disintegration time measured by the oral disintegrating tablet tester ODT-101 is less than 20 seconds, and the Japanese Pharmacopoeia General Test Method Dissolution Test Method 2 (50 min ^-1 , The elution rate (CDHP, 15 minutes) measured by 900 mL of the test solution water is a nucleus tablet having 90% or more, particularly preferably the wear damage of the nucleated tablet (accumulated rotational speed of 100 revolutions) is 0.2% or less, and the height is 2 m. Disintegration time measured by the intraoral disintegrating tablet tester ODT-101, having a shell which is substantially free from cracking or cracking in the drop test in This 1 It is a nucleated tablet with a dissolution rate (CDHP, 15 minutes) measured within 6 seconds and measured by the Japanese Pharmacopoeia General Test Method Elution Test Method 2 (50 min ⁻¹ , 900 mL of test solution water).

In addition, "hardness" is an index for evaluating tablet strength, and can be measured according to the method tablet breaking load (TABLET BREAKING FORCE) based on USP. That is, the circular tablet is pressed at a constant speed (20 N / sec or less or 3.5 mm / sec or less) between two parallel platens in the radial direction to measure the load when the tablet breaks. As hardness in the nucleus tablet of the present invention, 30N to 60N are preferable in consideration of the balance of disintegration properties, and more preferably 35N to 55N.

Examples of the additive to be contained in the shell of the nucleated tablet of the present invention include crystalline cellulose, lactose, hydroxypropyl cellulose and the like, in order to improve tablet strength, but preferably crystalline cellulose, lactose or a mixture thereof, More preferably, it is a mixture of crystalline cellulose and lactose. Moreover, in order to improve disintegration and dissolution property, it is preferable to contain a disintegrating agent, for example crospovidone, partially alpha starch, carmellose, corn starch, low-substituted hydroxypropyl cellulose, and more preferably. Is crospovidone and / or partially alphaated starch.

In this invention, it is preferable to use 30-65 mass% as the quantity of lactose used for a shell component, More preferably, it is 40-60 mass%, Especially preferably, it is 45-55 mass%. When the amount of lactose is less than 30% by mass, the disintegrability deteriorates, and when the amount of lactose is greater than 65% by mass, the wear damage tends to increase. It is preferable to use 30-50 mass% as quantity of crystalline cellulose, More preferably, it is 35-45 mass%. When the amount of crystalline cellulose is less than 30% by mass, the degree of abrasion damage increases, and when the amount of the crystalline cellulose is greater than 50% by mass, the disintegration property deteriorates, and the food touches the mouth. In addition, regarding the amount ratio of lactose and crystalline cellulose, in consideration of the balance between hardness, disintegration property and dosage of tablets, the amount of lactose and the amount of crystalline cellulose is more preferably 1: 0.5 to 1.5 in mass ratio, and 1: 0.8. It is especially preferable to set it as -1.3. As quantity of crospovidone, it is preferable to use 2.5-15 mass%, More preferably, it is 2.5-7.5 mass%. It is preferable to use it as 2-7.5 mass%, More preferably, it is 2.5-5 mass% as quantity of partially alphalated starch.

About the inner core of the nucleated tablet of this invention, it is also possible to comprise only the active ingredient containing tegapur, gimeracil, and oteracil potassium. As a compounding quantity of an active ingredient, it can occupy 50 mass%-100 mass% of an inner core component, Preferably, it occupies 70 mass%-99 mass%. In addition, in order to provide adequate tablet strength and disintegration, an appropriate amount of pharmaceutically acceptable binder and / or disintegrant may be added. The binder is not particularly limited as long as it is a binder used in pharmaceutical preparations. For example, starch solution, methyl cellulose, hydroxypropyl cellulose (HPC-SSL, HPC-SL, HPC-L, etc.), hydroxypropyl methyl cellulose, Sodium carboxymethyl cellulose (sodium carmellose), gum arabic, gelatin, agar, tragacanth, sodium alginate, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol and the like, and these It can also be used in combination of 2 or more type, Preferably it is hydroxypropyl cellulose. The content of the binder may be added in an amount of 0.1 to 2.0 mass%, more preferably 0.4 to 1.0 mass%, based on the total amount of tegapur, gimeracil, and terrasil potassium. Moreover, as a disintegrating agent, carmellose, carmellose calcium, croscarmellose sodium, crystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, etc. are mentioned, for example, These are 1 type, or 2 or more types It can also be used in combination, Preferably it is crospovidone. It is preferable that content of a disintegrating agent is 3-15 mass% with respect to the total amount of tegafur, gimeracil, and terasil potassium.

In addition, a small amount of disintegration aids can be added to the inner core, and examples of disintegration aids include carmellose, carmellose calcium, sodium carmellose, croscarmellose sodium, and low-substituted hydroxypropyl cellulose and carboxymethyl. Sodium starch, corn starch, potato starch, alpha starch, partially alpha starch, hydroxypropyl starch, crospovidone, sodium lauryl sulfate, polysorbate, polyoxyethylene polyoxypropylene glycol, sorbitol monooleate, mono Propylene glycol stearate, polyethylene glycol monolaurate, etc. are mentioned, You may use these 1 type or in combination of 2 or more types.

In addition to the additives described above, the nucleated tablet of the present invention may contain various agent additives which are generally used in a range that does not interfere with the effects of the present invention. There is no restriction | limiting in particular if it is a thing generally used as a formulation additive, For example, a lubricant, a coloring agent, a flavoring agent, a mating agent, etc. are mentioned. Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, and sucrose fatty acid esters. Examples of the coloring agent include edible yellow pigment 5, edible red pigment 2, edible blue pigment 2, edible lake pigment, yellow ferric trioxide, titanium oxide and the like. Examples of the flavoring agent include oranges, lemons, various flavors, and the like. L-menthol, camphor, mint, etc. are mentioned as a mating agent.

The nucleated tablet of the present invention is, for example, nucleated tableting machines such as tablet press LIBRA2 DC (manufactured by Kikusui Seisakusho), AP-MS-C nucleus tableting machine (manufactured by Hatake Tekkosho), and further, autograph AG-E50k. (Shimadzu Seisakusho Co., Ltd.) etc. can be manufactured. That is, as a general manufacturing method thereof, it is largely composed of four steps, (i) feeding a part of the outer shell component into the mortar, (ii) supplying the inner core pre-prescribed to the mortar, (iii) supplying the remaining outer shell component to the mortar, (iv) It can manufacture by pressure-molding between a mortar and an upper and lower mortar. In addition, International Publication 2003-28706, J. Jpn. Soc. Pharm. Mach. & Eng. 14 (4), 12-21 (2005)] and the tablet press of a rotary compression molding machine (Sangawa Chemical Co., Ltd.), etc., and the tablet which has a double structure of an inner core and an outer shell can be produced high productivity. The manufacturing method is also preferable at the point which can be easily shape | molded. That is, the nucleated tablet of the present invention has a pestle in both the upper and lower sides of the mortar, at least the upper pestle, including a double structure of the outer pestle surrounding the center and the center of the hole, It can be manufactured easily by the compression shaping | molding means which can be slid simultaneously and a compression operation | movement can be performed both of a center pick ball and an external pick ball. As described above, since the nucleated tablet of the present invention can be produced by one tableting machine at a time, it can be produced efficiently without performing a complicated technique and process as in the prior art. Therefore, there is no positional shift of the nucleus as in the conventional nucleated tablet, and it is possible to make the shell very thin. In particular, it is possible to make the thickness of the outer skin 1 mm or less. The thinning of the shell also contributes to the improvement of the collapse of the nucleus tablet.

The shape of the nucleated tablet of the present invention may be a shape that is easy to be caught or has no discomfort when taken, and the shape thereof is not particularly limited, but is preferably a round or elliptical preparation similar to a general medicine. Its size may also be such that it can be inserted into the oral cavity and does not involve difficulty in chewing. For example, if it is a circular tablet, it may be about 25 mmφ or less, and it can be designed so that it may be 4-25 mmφ, Preferably it is 6-16 mmφ, More preferably, it is 7-12 mmφ. The height of the formulation can be on the order of 10 mm or less, and can be designed to be 1 to 10 mm, preferably 1.5 to 7 mm, more preferably 2 to 5 mm.

The shape of the inner core depends on the tip shape of the cut hole used, and corresponds to the shape of the nucleated tablet. The size of the inner core is often dependent on the size of the whole nucleus tablet, and in order to perform the shaping process of the inner core smoothly, it is not desirable to be too small. In addition, in order to improve the disintegration property of the nucleated tablet, it is preferable to enlarge the inner core with respect to the outer skin in the range which does not interfere with shaping | molding of a shell. Therefore, the inner core may be about 24 mmφ or less if it is a circular tablet, and may be designed to be 3 to 24 mmφ, preferably 5 to 15 mmφ, more preferably 6 to 11 mmφ. In addition, an inner core can also be divided into several parts as needed.

According to the size of the inner core, the thickness of the outer shell is low in abrasion damage, and can be set to a thickness in which the shape of the nucleated tablet can be held by the outer shell, and is preferably set within the range of 0.2 to 2 mm. In order to increase quick disintegration in the oral cavity, it is better not to increase the tablet strength of the skin portion more than necessary. Therefore, it is preferable to make the thickness of the shell as thin as possible in a range where the problem of attrition damage does not occur, that is, the shape of the nucleated tablet can be maintained, and it is realistic and preferable to set it to 0.5 to 1.5 mm.

As the nucleated tablet of the present invention, a nucleated tablet having an inner core of 3 to 24 mmφ, a shell having a thickness of 0.2 to 2 mm, and a formulation having a height of 1 to 10 mm is preferred, and an inner core having a core of 5 to 15 mmφ and a shell having a thickness of 0.5 to 2 mm. More preferred are nucleated tablets having a height of 1.5 mm and a formulation of 1.5 to 7 mm, particularly preferred are nucleated tablets having an inner core of 6 to 11 mmφ, a shell thickness of 0.5 to 1.5 mm, and a formulation having a height of 2 to 5 mm. .

<Examples>

Hereinafter, the present invention will be described in more detail with reference to Examples, Examples, and Test Examples, but the present invention is not limited thereto. In addition, tegapur and gimerasil used in the said Example are the Daiho Yakuching High School Co., Ltd., and Oteracil potassium is the Sumitomo Chemical Co., Ltd. product. In addition, hydroxypropyl cellulose (HPC) is manufactured by Nihon Soda Co., partially alpha starch and crystalline cellulose are manufactured by Asahi Kasei Chemicals Co., Ltd., magnesium stearate is manufactured by Taihei Chemical Co., Ltd., and Crospovidone is manufactured by BASF Co., Ltd. .

Reference Example 1 (Manufacture 1 of Inner Core Components)

Using a fluidized bed granulator multiplex MP-01 (manufactured by Faurex), 66.1 g of tegapur, 19.15 g of gimeracil, 64.75 g of potassium terasil, and 150 g of lactose (manufactured by Boccolo Domo Independents) The mixture was sprayed with 200.0 g of water and granulated to prepare an inner core component.

Reference Example 2 (Manufacture 2 of Inner Core Components)

In the same manner as in Reference Example 1, 1.0 g of HPC was added to a mixture of 66.1 g of tegapur, 19.15 g of gimeracil, 64.75 g of potassium terrasil, and 150 g of lactose (manufactured by Boccolo Domo Independents). The solution dissolved in g was sprayed and granulated to prepare an inner core component.

Reference Example 3 (Manufacture 3 of Inner Core Components)

In the same manner as in Reference Example 1, 200 g of water was sprayed and granulated to a mixture of 132.2 g of tegapur, 38.3 g of gimeracil, and 129.5 g of potassium teracil to prepare an inner core component.

Reference Example 4 (Manufacture 4 of Inner Core Components)

In the same manner as in Reference Example 1, a mixture of 132.2 g of tegapur, 38.3 g of gimeracil, and 129.5 g of terrasil potassium was sprayed with a solution obtained by dissolving 0.3 g of HPC in 199.7 g of water, and granulated to provide an inner core component. Prepared.

Reference Example 5 (Manufacture 5 of Inner Core Components)

In the same manner as in Reference Example 1, to a mixture of 132.2 g of tegapur, 38.3 g of gimeracil, and 129.5 g of terrasil potassium, a solution of 1.5 g of HPC dissolved in 198.5 g of water was sprayed and granulated to prepare an inner core component. Prepared.

Reference Example 6 (Manufacture 6 of Inner Core Components)

In the same manner as in Reference Example 1, a mixture of 132.2 g of tegapur, 38.3 g of gimeracil, and 129.5 g of potassium terasil potassium was sprayed with a solution obtained by dissolving 3.0 g of HPC in 197.0 g of water, and granulated to provide an inner core component. Prepared.

Reference Example 7 (Manufacture of Inner Core Components 7)

In the same manner as in Reference Example 1, a mixture of 132.2 g of tegapur, 38.3 g of gimeracil, and 129.5 g of potassium terasil potassium was sprayed with a solution of 4.5 g of HPC dissolved in 195.5 g of water, and granulated to provide an inner core component. Prepared.

Reference Example 8 (Manufacture 8 of Inner Core Components)

In the same manner as in Reference Example 1, to a mixture of 132.2 g of tegapur, 38.3 g of gimeracil, and 129.5 g of terrasil potassium, a solution of 6.0 g of HPC dissolved in 194.0 g of water was sprayed and granulated to prepare an inner core component. Prepared.

Reference Example 9 (Manufacture 9 of Inner Core Components)

In the same manner as in Reference Example 1, 4 g of HPC was added to a mixture of 200 g of tegapur, 58 g of gimeracil, 196 g of potassium terrasil, and 14 g of partially alphaated starch (manufactured by Asahi Kasei Chemicals Co., Ltd.). The solution dissolved in g was sprayed and granulated to prepare an inner core component.

Reference Example 10 (Manufacture 10 of Inner Core Components)

In the same manner as in Reference Example 1, to a mixture of 200 g of tegapur, 58 g of gimeracil, and 196 g of potassium teracil, a solution of 4 g of HPC dissolved in 396 g of water was sprayed and granulated to prepare an inner core component. Prepared.

Example 1

Using autograph AG-E50k (manufactured by Shimadzu Corporation), 59.88 mg of lactose (manufactured by Meggle Excellence and Technology Co., Ltd.), 60 mg of crystalline cellulose, and 0.12 mg of magnesium stearate were used as an outer shell. A mixture of 2.84 mg of partially alpha starch and 0.28 mg of magnesium stearate was added to 57 mg of the granule of 5 (25 mg as tegapur) as the inner core, 30 mg of the outer layer of the outer shell, 60.12 mg of the inner core, and additionally the shell agent. It was filled with 60 mg of two layers in order, and the nucleated tablet with the tablet outer diameter of 8 mm was produced at tablet pressure of 5 kN. The schematic diagram of the cross section of the obtained nucleated tablet is shown in FIG. The inner core diameter of the obtained nucleated tablet was 6 mm, and the thickness (a) of the shell was 1 mm.

Example 2

Using autograph AG-E50k (manufactured by Shimadzu Corporation), lactose 53.76 mg (manufactured by Meggle Experts and Technologies), 60 mg of crystalline cellulose, 6 mg of crospovidone, and magnesium stearate 0.24 in the same manner as in Example 1. An outer shell was used as the inner core, with a mixture of the ratio of mg as the inner shell and a mixture of 2.84 mg of partially alpha starch and 0.28 mg of magnesium stearate added to 57 mg of the granule of Reference Example 5 (25 mg as tegapur). Nucleated tablets containing 25 mg of tegapur were prepared at mg, inner core 60.12 mg, and tablet pressure 5 kN. The obtained nucleated tablet had an outer diameter of 8 mm, an inner core diameter of 6 mm, and an outer shell thickness of 1 mm.

Example 3

Using the autograph AG-E50k (manufactured by Shimadzu Corporation), a desired nucleated tablet was produced by the same manufacturing method as in Example 1, except that the inner core components of Reference Examples 1 to 4 and 6 to 10 were used.

Example 4

Using a rotary compression molding machine (manufactured by Sanwa Chemical Industries, Ltd.) as described in International Publication No. 2003-28706, the mixture was mixed at a ratio shown in Table 1, and 57.25 mg of the granulated product of Reference Example 10 was obtained. 25 mg) was added to the mixture of 1.5 mg crospovidone, 1.5 mg partially alpha starch, 1.5 mg coagulation agent, and 0.25 mg magnesium stearate as the inner core component, the outer layer 1 layer, inner core 62 mg, and additional shell 2 Filled in the order of the layers (amount of the outer shell 1 layer: the amount of the outer shell 2 layer = 35:85) to prepare nucleated tablets 1 to 4 having a tablet outer diameter of 8 mm at a tablet pressure of 4 kN.

Test Example 1

The nucleated tablets 1 to 4 obtained in Example 4 were subjected to hardness, abrasion damage, oral disintegration test, and dissolution test. The results are shown in Table 1. As a result, 34 to 64% by mass lactose, 30 to 50% by mass of crystalline cellulose and 5 to 15% by mass of crospovidone were excellent in terms of hardness, abrasion damage, oral disintegration, and dissolution ability. It was confirmed that it was a nucleated tablet.

<Test Conditions>

Hardness Tablet Durometer Tablet Tester 8M, Schlenizer Manufacturer

Abrasion damage tablets Abrasion damage tester 100 revolutions (25 rpm, 4 minutes)

Collapse test Japan Pharmacopoeia General Test Method Collapse Test Method Test Solution Water

Intraoral disintegration test Intraoral disintegration tester ODT-101, Toyama Chemical Industries, Ltd. spindle φ 20 mm 20 g, rotation speed 75 rpm, test liquid water

Dissolution test Japanese Pharmacopoeia General Test Method Elution Test Method 2 (50 min ^-1 ), Test Solution 900 mL

Example 5

Using the same rotary compression molding machine (manufactured by Sanwa Chemical Industries, Ltd.) in the same manner as in Example 4, the inner core component was produced by the same manufacturing method as in Example 4 by mixing the mixture in the ratio shown in Table 2, and the outer shell first layer. , 60 mg of inner core, further filled in the order of the outer shell 2 layer (amount of the outer shell 1 layer: the amount of the outer shell layer = 35:85), 5 to 5 nucleated tablets of tablet outer diameter 8 to tablet pressure 8 was prepared.

Test Example 2

With respect to the nucleated tablets 5 to 8 obtained in Example 5, hardness, wear damage, oral disintegration test, and dissolution test were performed. The results are shown in Table 2. As a result, hardness, abrasion damage, oral disintegration property in 39-59 mass% of lactose for direct hitting, 30-50 mass% of crystalline cellulose, 2.5-7.5 mass% of crospovidone, and 2.5-7.5 mass% of partially alpha starch, And it was confirmed that it is an excellent nucleated tablet from the viewpoint of dissolution property.

<Test Conditions>

Hardness Tablet Durometer Tablet Tester 8M, Schlenizer Manufacturer

Abrasion damage tablets Abrasion damage tester PTF30ERA, Pharmatest Afaratebau manufactured 100 rotations (25 rpm, 4 minutes)

Collapse test Japan Pharmacopoeia General Test Method Collapse Test Method Test Solution Water

Intraoral disintegration test Intraoral disintegration tester ODT-101, Toyama Chemical Industries, Ltd. spindle φ 20 mm 20 g, rotation speed 75 rpm, test liquid water

Dissolution test Japanese Pharmacopoeia General Test Method Elution Test Method 2 (50 min ^-1 ), Test Solution 900 mL

Example 6

Using the same rotary compression molding machine (manufactured by Sanwa Chemical Industries, Ltd.) as in Example 4, the mixture was mixed at a ratio shown in Table 3, and 45.8 mg of the granulated material of Reference Example 10 (20 mg as the amount of tegapur) was used. To the inner core component, a mixture in which 2 mg of crospovidone, 0.4 mg of partially alpha starch, 1.2 mg of copulation agent, and 0.2 mg of magnesium stearate was added was used as the inner core component, followed by the outer layer 1 layer, the inner core 49.6 mg, and then the outer layer 2 layer. After filling (amount of the outer layer 1: the amount of the outer layer 2 = 30:66), nucleated tablets 9 to 12 having a tablet outer diameter of 8 mm were prepared at a compression pressure of 4 kN.

Test Example 3

The nucleus tablets 9 to 12 obtained in Example 6 were subjected to hardness, abrasion damage, oral disintegration test, and dissolution test. The results are shown in Table 3. As a result, hardness, abrasion damage, oral disintegration property in 39-59 mass% of lactose for direct hitting, 30-50 mass% of crystalline cellulose, 2.5-7.5 mass% of crospovidone, and 2.5-7.5 mass% of partially alpha starch, And it was confirmed that it is an excellent nucleated tablet from the viewpoint of dissolution property.

Test Example 4

About the nucleated tablets 6-8 obtained in Example 5 and commercially available orally disintegrating tablets (A company, B company, C company, D company, E company), the tablet drop test which naturally falls to a stainless steel plate from a height of 1 m Was carried out. The results are shown in Tables 4 and 5. As a result, it was confirmed that the nucleated tablets 5 to 8 were superior nucleated tablets in terms of cracking, cracking, and mass loss rate compared to commercially available oral disintegrating tablets.

<Test Conditions>

Tablet drop test stainless steel plate, height 1m (five)

Claims (17)

A nucleated tablet comprising (a) tegapur, (b) gimeracil and (c) inner core containing potassium terasil as an active ingredient and an outer shell. The nucleated tablet according to claim 1, comprising (a) tegapur, (b) gimeracil, and (c) potassium terrasil in a molar ratio of 1: 0.4: 1. The oil according to claim 1 or 2, wherein an active ingredient comprising (a) tegapur, (b) gimeracil, and (c) potassium terasilyl occupies 50% by mass to 100% by mass of the inner core component. Nuclear tablet. The active ingredient according to any one of claims 1 to 3, wherein the active ingredient comprising (a) tegapur, (b) gimeracil, and (c) potassium terasilyl is 70% to 99% by mass of the inner core component. Nucleated tablets account for%. The nucleated tablet according to any one of claims 1 to 4, wherein the total content of the active ingredients (a) to (c) in the nucleated tablet is 10 to 60 mass%. The nucleated tablet according to any one of claims 1 to 5, wherein the shell comprises one, two, or three of lactose, crystalline cellulose, and hydroxypropyl cellulose. 7. The nucleated tablet according to claim 6, wherein the shell comprises one or two of lactose and crystalline cellulose. 8. The nucleated tablet according to claim 7, wherein the shell comprises lactose and crystalline cellulose. The nucleus tablet according to any one of claims 6 to 8, further comprising a disintegrant in the shell. The nucleated tablet according to claim 9, wherein the disintegrant is selected from the group consisting of crospovidone, carmellose, corn starch, low-substituted hydroxypropyl cellulose, and partially alpha starch. The nucleated tablet according to claim 10, wherein the disintegrant is crospovidone and / or partially alphaated starch. The nucleated tablet according to any one of claims 1 to 11, wherein the shell comprises 30 to 65 mass% lactose. The nucleated tablet according to any one of claims 1 to 12, wherein the shell comprises 30 to 50 mass% of crystalline cellulose. The nucleated tablet according to any one of claims 1 to 13, wherein the shell comprises 2.5 to 15 mass% crospovidone. The nucleated tablet according to any one of claims 1 to 14, wherein the shell comprises 2 to 7.5% by mass of partially alphalated starch. The wear damage of the nucleus tablet (accumulated rotational speed of 100 revolutions) is 0.3% or less, and the collapse time according to the Japanese Pharmacopoeia General Test Method Disintegration Test Method is 120 seconds. A nucleated tablet characterized by the following. The shell according to any one of claims 1 to 16, wherein the nucleation tablet has an abrasion damage degree (accumulated rotational speed of 100 revolutions) of 0.2% or less, and is substantially free of cracks or cracks in a drop test at a height of 1m. The nucleus well which has a collapse time of 95 seconds or less by the Japanese Pharmacopoeia General Test Method collapse test method.

Images